Androgen ablation therapy is the first line treatment for metastatic prostate cancer (PCa). Despite this treatment, PCa will eventually progress to an androgen refractory stage. Although there is no effective therapy for androgen refractory PCa, the androgen receptor (AR) continues to play a role at this stage of the disease. Indeed, at this stage the AR is sensitized to low androgen levels, and can also be activated by non-androgenic factors such as the cytokine, interleukin-6 (IL-6). Several studies, including our own, indicate that de-regulation of AR coregulatory proteins plays an important role in this promiscuous transcriptional activation of the AR. We have shown that, following IL-6 stimulation of PCa cells, components of the MAPK pathway are phosphorylated, thus leading to AR transcriptional activation. We have shown that the coactivator p300 mediates this IL-6-dependent AR transcriptional activation. Our preliminary data also shows that androgens, through the AR, positively regulate expression of the AR. coactivator, FHL2, while negatively regulating expression of the nuclear receptor corepressor, RIP140. Furthermore, we have observed increased FHL2 expression and reduced RIP140 expression in cell-based models of advanced prostate cancer. Our data also suggest that FHL2 plays a role in conjunction with p300 in transcriptionally activating the AR in response to IL-6. We thus hypothesize that the coregulators p300, FHL2, and RIP140 play important roles in AR transcriptional activation during androgen refractory progression of PCa. We suggest that in androgen-dependent PCa, RIP140 forms a complex with the AR, thus limiting the activation of the AR to androgens. However, upon androgen stimulation, or when PCa progresses to an androgen refractory stage, this complex is lost. This de-repression would then allow non-androgenic factors such as IL-6 to induce complex formation between the AR, p300, and FHL2. To test this hypothesis, we propose to (1) determine the role of the p300/FHL2 complex modulated through the MAPK pathway in the IL-6 mediated regulation of the AR;(2) determine the role of RIP140 in the IL-6 mediated regulation of the AR;and (3) determine the role of AR-mediated FHL2 induction and RIP140 repression in androgen dependent and refractory PCa. These studies should enhance our understanding of the mechanisms involved in androgen refractory PCa, and may lead to the identification of new therapeutic targets.